Currently, there are no effective treatments for human cocaine addiction, underscoring the need for additional treatment strategies. A novel strategy we focus on in the present proposal makes use of the normal daily rhythms that we and others have found to alter sensitivity to the rewarding effects of drugs such as cocaine. The suprachiasmatic nucleus (SCN) is a prime candidate for generating these time-of-day effects. The SCN neurons and their projections to other brain regions, including the ventral tegmental area (VTA), nucleus accumbens and medial prefrontal cortex (mPFC), synchronize behaviors to the daily light:dark cycle. The so-called clock genes generate the daily oscillation in SCN activity. Forebrain neurons implicated in addictive behaviors also express clock genes, and may be entrained by the SCN. However, we do not know if the SCN alone produces the time-of-day variation in cocaine-seeking behavior, or if time- of-day effects on cocaine-seeking are also influenced by clock genes in dopaminergic brain regions. The proposed studies will directly examine the contribution of the SCN and CLOCK protein expression in the SCN and VTA on cocaine-seeking behavior. Our recent studies indicate a strong influence by the SCN for time-of-day effects on extinction of cocaine-seeking behavior in a conditioned place preference (CPP) paradigm. In addition, time-of-day effects on cocaine-primed reinstatement of CPP appear to be influenced by rhythms originating outside the SCN. We have also discovered diurnal variation in expression of the dopamine transporter (DAT) protein. We propose the following three Specific Aims: 1) Determine the contribution of the SCN and photoperiod to time-of-day variation in the extinction rate of cocaine-induced CPP and DAT protein levels 2) Determine the contribution of extra-SCN dopamine brain regions and photoperiod to time-of-day variation in the reinstatement of cocaine-induced CPP 3) Determine the contribution of CLOCK protein in the SCN and VTA neurons to the time-of-day variation in reinstatement of cocaine CPP Aims 1 and 2 will use sham and SCN-lesioned rats and test cocaine extinction and reinstatement under constant darkness to define the role of the SCN and extra-SCN brain regions on time-of-day variation in cocaine-seeking behavior. Aim 3 will use antisense oligonucleotides injected in the SCN and VTA to assess the influence of clocks in these regions on time-of-day variation in cocaine-seeking behavior. Relevance to Public Health: The proposed work is significant because it is expected to provide knowledge that can be used to develop novel treatment approaches for cocaine and perhaps other drug addictions. In addition, the knowledge gained is expected to offer insight into the individual differences in susceptibility to relapse in humans.PROJECT NARRATIVE Currently, there are no effective treatments for human cocaine addiction, underscoring the need for additional treatment strategies. A novel strategy we focus on in the present proposal makes use of the normal daily light:dark rhythms that alter sensitivity to the rewarding effects of drugs such as cocaine. Our contribution will be to provide detailed information about the regulation of time-of-day variation in cocaine- seeking behavior by the major biological clock and other brain regions. Such knowledge is significant because it will provide the means to develop novel treatment approaches for cocaine and perhaps other drug addictions.